Composition of matter and method



Patented Sept. 24, 1946 uNiTEbf ST T oomrosrrroufonm'rrnn AND METHOD. Robert S. Sheltom Mariernont, and Marcus G.

3 Van Campen, (in, Deer Park, Ohio, 'assignors to The Wm. S.. Merrell Company, Cincinnati, Ohio, a'corporation of Ohio] 1 .No Drawing. Application April is, 1942,

' serial No.438 ,728

7 I j s Claims (01. 260-5701;)

This. invention relates to novel chemical compounds, methods of -'making .the. same, and to pharmaceutical preparations in which: one or more of said compounds is anactive ingredient.

chemical compounds useful as pharmaceuticals and as intermediateslfiori manufacture ofv other hmic'als.

I Another object of the invention, is to provide effective vasopressor compositionshaving' little or no stimulating effect. 3 1 f 7 Another object of the invention is to provide a method of synthesizing alpha di-substituted ethane amines, 1 and particularly beta-phenyl-. 'ha-.alpha-dimethyhalpha-amino ethane, (ala-benzyl'isopropylamine): It. has been known, here Stltuted riva s o .'betaeph amif ethanes, are activefpharmaceutical compounds exhibiting vasopressor or vasodilator, mydriatic, sympathomimetic, and/or central stimulant properties in varying degrees. In many cases it is desirable to produce one of these effects without others ;'thus,'in particularit is frequently desirable in cases of common cold and hay fever to shrink the nasal mucosa by application of a vasoconstrictor composition; whereas, any accompanying central stimulant efiect maybe quite undesirable, particularly as it interferes with sleep. By the present invention we have made available a vaso-pressor amine of the'substituted betaphenyl-amino ethane type which has extraordinarily good activity and duration as a vasopressor, mydriatic, etc, but with only slight central stimulant effect.

In our' efiorts to test this, however, we were faced with great difliculty in that noneof the common reactions used for producing other amines of this general class provedsatisfactory for production" of thisparticularflamine;

Analogous chlorides could be -made bf1t,' presumably due to stearic hindrance from the methyl groups on the alpha-carbon atom, the chloride could not be converted to the amine byordinary methods. Also the beta-phenyl-beta hydroxyalpha-alphaedimethyl-alpha-amino ethane is known and is commercially available. 7 This product can be made, for example, byl 'ondensation of benzylaldehyde with nitroproparie, and rene object oi the invention is'to produce novel tofore that manysub -2 duction-of the resulting nitro compound to the corresponding amino compound, but it had not proven practical to directly eliminate the hydroxy group. r We have now discovered that the desired betaphenyl-alpha-alpha-dimethyl-alpha-amino ethane compound can be made by catalytic reductionof the corresponding chloro compound, betaphenyl-beta-chloro-alpha-alpha-dimethyl-alpha- 10 amino ethane, advantageously in the presence of an alkali adaptedto react with the chlorine released froin such compound by the reduction.

, Surprisinglmthe resulting compounds, whether asfree amineor in the form of the non-toxic salts, have proven to be relatively inactive as central stimulants but very valuableas a vasopressor; and thus, surprisingly, the synthesis of this compound supplies an important need for a vasopressor' with only slight central stimulant effect. Although we are giving below certain specific examplesof our invention and its application in practical use and. are giving also certain modifications and alternatives, it should be understood that these are not intended to be exhaustive nor limiting of the invention. On the contrary we are givingthese as illustrations and are giving herewith explanations in order fully to acquaint others skilled in the art with our invention and the principles thereof and a suitable manner of its application in practical use, so that others skilled in the art may be enabled to modify the invention and to adapt it and apply it in numerous forms, each as may be best suited to the requirements of a particular use. i

I. As an example of the use of these materials a composition particularly suitable for use as a nasal inhalant may be made as follows:

. Parts Menthol 1 Camphor 1 Beta-phenyl-alpha-alpha-dimethyl-alphaamino-ethane .(as the free amine) 8 The camphor and menthol are dissolved inthe amine and the-solution applied to a pledget of cotton and placed in. an inhaler device. The proportions of menthol and camphor may be varied rather widely and they may be replaced'by other suitable aromatic or mixture of aromatic subo'stancessuchas euoalyptol', oiloi lavender, oil of 3 rose, etc. Likewise, the proportion of the amine may be increased or decreased substantially.

II. A suitable material for use as aqueous base nose drops may be made as follows:

Distilled water, q. s.

We prefer to use organic acidsalts rather. than 1'3: .Amiktlire equal parts by Weight of beta 'fpheriyl betaehydroxy-alpha-amino-alpha-methyl mineral acid salts, since in general they are. less irritating.

I. The surface tension of the material is approx imately 34.5 dynes per sq. centimeter.

III. A suitable composition 'f01 wusejas an oil base nose'drop may be made as follows;

, u Parts Beta-phenyl-alpha alpha-dimethyl-alphaamino ethane 0.5 Oil of eucalyptus a i 1.0 Mineral oil 98.5

. d 1 Per cent Beta phenyl alpha alpha dimethylalpha-amino ethane 0.5

Cetyl Dyridinium chloride W. 0.1 Tragacanth j 1.0 Glycerine 15.0 Methyl salicylate 0.005 Eucalyptol 0.005 Oil dwarf pine needles 0.005 Distilled water 83.25

V. For internal administration the compound may be included in tablets of suitable composition, for example:

Beta-phenyl-alpha alpha dimethyl-alphaamino ethane mgs. per tablet 25 Mixed in a base consisting of approximately:

Parts Milk sugar 50 Cornstarch Talc 1 Stearic acid 1 Acacia 10 And compressed into anuncoated tablet of approximately 2.8 grains.

Instead of compounding'the amine in a tablet base it may be added to a suitable syrup or other vehicle for internal administration. I

As will be appreciated from the above the use of this amine compound is'very similar to other ,vasopressor amines and in general may be used in the same manner. Those skilled in the art will The sorbitol in this composition serves to make the product isotonic and should. be in amount adjusted to eiTect that result. "Tllfi pH of the solution is adjusted to approximately" 4 have no difiiculty in utilizing it in widely different types of compositions and substituting it in such compositions for previously used amines of this general class.

The corresponding secondary amine is similarly valuable for the same purposes.

The following example will illustrate a method of preparing this compound in accordance with my invention although, as will be evident to those skilled in the art, various equivalent substances may be used. in place of those mentioned and various equivalent procedures may be used instead of the particular steps described:

Preparation of beta-phenyl-beta-chZoro-alphaaminoalpha-alpha-di-methyl ethane hydrochloride 2o propane hydrochloride and thionyl chloride are allowed'to standat ordinary temperature 7 35 C.) for 10 to 15 hours, then warmed to 70 C. -The solid which results is then powdered and washedwith 200 to 300 cc, of ligroin, and finally dried over soda lime. The resultingbeta-phenylbeta-chloro-MDhal-amino -alpha-methyl -propane hydrochloride is aboutv 95% pure: and is often satisfactory for use in. the next step, but is advantageously purified before further use For purification 60 parts ofthe crude material is disdrog'en at 50- 80 C. and under-.50 lbs. pressure solved in 120 parts of; hOtffllCOhOlf and {poured into 360 parts of ether, cooled, and thepure hydrochloride Salt filtered and dried. Tn yield of purified material lS abOl,lt 80% ofthe theory.

Preparation '0} beta-phenylealiihaeaminoealphae 'alphaedimethyz 1 5 parts of the above beta-phenyl beta-chloroe alpha-amino-alpha alpha-dimethyl ethane hy- 40 drochloride, are dissolved iii-150 partslofalco i hol, and 5 parts ,of palladiniz'ed .calciumfcarbonate added. 'The mixtures then reduced in a conventional hydrogenation apparatus with'hy- When hydrogeh is no 3 longer readily absorbed,

the solutionis removed, the. palladiniz'edcalcium carbonate filtered andthe' filtrate evaporated.

The residue is dissolvedin'dilutehydrochloric j acid, shaken with ether and'the ether "discarded. Theacid solution is then made. alkaline, as with sodium hydroxide, and the-amine extracted with ether. The ether solutionmay (1) be dried and distilled to give the desired 'a-ben'zyl isopropyl amine, B. P. 205 at 750 mm. or 100 at 21.mm.

or (2) the ether solution may be dried and saturated with hydrogen chloride an'dthe preci itated hydrochloride recrystallizedfroma mixture of 50 parts alcohol and 100- parts of acetone.

- The pure hydrochlorideis thus obtained as a white crystalline substance in yieldsf60%, of the theoretical and having a,M,.P of -106 C..unc. Other halogeno compounds may. be usedinstead yield of the novel product, beta-cyclohexyl-alphaalpha-dimethyl-alpha-amino ethane.

Accordingly, regardless of which of two types of catalysts is employed, the method is utilizable acid from the amine group as thatwould permit the amino-ethane compound to react with itself. As indicated above and as generally recognized with the class of vasopressor amines they may be used either as free amines or as amine salts and as primary or secondary amines.

What is claimed is: 1. The method of preparing beta-phenyl-alpha-alpha-dimethyl-aminp ethane and the amine salts thereof which comprises hydrogenating the corresponding beta-phenyl-beta-chloro-alphathereof which comprises hydrogenating betaphenyl beta chloro alpha alpha dimethylamino-ethane hydrochloride in solution in the presence of palladium absorbed on calcium carbonate.

4. The method-of preparing beta-phenyl-alpha-alpha-dimethyl-alpha-amino ethane and the amine salts thereof which comprises hydrogenating the corresponding beta-phenyl-beta-betachloro-alpha-methyl-alpha-amino propane at elevated temperature and pressure in alcoholic solution in the presence of palladinized calcium carbonate dispersed therein.

5. The method of preparing beta-phenyl-alphaalpha-alpha-amino ethane and the amine salts thereof which comprises hydrogenating betaphenyl-beta-chloro-alpha-methyl alpha amino propane at atemperature between about 50-80 alpha-dimethyl-amino ethane compound in solution in the presence of a catalytic metal of the class consisting of platinum and palladium absorbed on a basic carrier.

2. The method of preparing beta-phenyl-alpha-alpha-dimethyl-amino ethane and the amine salts thereof which comprises hydrogenating-betaphenyl-beta-chloro-alpha-alpha-dimethyl-amino ethane hydrochloride in solution in the presence of palladium absorbed 0n magnesium carbonate.

3. The method of preparing beta-phenyl-alphaalpha-dimethyl-amino ethane and the amine salts C.v andpa hydrogen pressure about lbs. per square inch and in alcoholic solution with finely divided palladinized calcium carbonate dispersed therein.

'6. The method of preparing beta-phenyl-betachloro-alpha-alpha-dimethyl-amino ethane and the amine salts thereof which comprises mixing a corresponding beta-phenyl-beta-hydroxy-alpha-alpha-dimethyl-amino ethane compound and thionyl chloride, allowing the same to react, warming, washing, and drying.

7. Beta-phenyl-alpha-alpha-dimethyl alphaamino ethane.

8. Beta-phenyl-alpha-alpha-dimethyl alphaaminoethane and the salts thereof.

ROBERT S. SHELTON'. MARCUS G. VAN CAMPEN, J R.

Certificate of Correction Patent No. 2,408,345. September 24, 1946.

ROBERT S. SHELTON ET AL.

It is hereby certified that errors appear in the printed specification of the above numbered patent requiring correction as follows: Column 4, line 37, after alphadimethy insert ethane; column 6, line 9, claim 4, after phenylstrike out beta-; line 15, claim 5, for alpha-alpha read alpha-dimethyl-alpha; and that the said Letters Patent should be read with these corrections therein that the same may conform to the record of the case in the Patent Office.

Signed and sealed this 8th day of April, A. D. 1947.

LESLIE FRAZER,

First Assistant Oonwnissioner of Patents. 

